The aim of any immunotherapeutic treatment is to minimize nonspecific toxicity, thus utilizing the body's own mechanisms to target and kill abnormal cells. Immunotherapy can be used to prime and amplify antigen-specific lymphocytes either in vivo (active iummunotherapy) or ex vivo prior to their infusion (adoptive immunotherapy). Adoptive immunotherapy is a procedure whereby an individual's own lymphocytes are expanded ex vivo and re-infused back into the body. Both adoptive and active immunotherapy can be used as therapeutic strategies for the treatment of viral infection (Papadopoulos, et al., N. Engl. J. Med, 330(17):1185-91 (1994); Savoldo, et al., Leuk Lymphoma, 39(5-6):455-64 (2000)), autoimmune disease (Hori, et al., Adv. Immunol., 81:331-71 (2003); Karim, et al., J. Immunol., 172(2):923-8 (2004)), or cancer (Dudley, et al., Nat. Rev. Cancer, 3(9):666-75 (2003); Riddell, et al., Cancer Control, 9(2):114-22 (2002); Yee, et al., Proc. Natl. Acad. Sci. USA., 99(25):16168-73 (2002)).
The process of antigen-specific activation, expansion and differentiation that is essential to the establishment of immunity is determined to a large extent by the interaction between T cells and antigen-presenting cells (APCs). Efficient stimulation of antigen-specific T cells depends on the interaction of the T cell antigen receptor (TCR) with specific antigen in the form of a peptide/major histocompatibility complex (pMHC) on APCs. In addition to this recognition signal, co-stimulation through the B7 family of receptors on APCs, which engage the CD28 receptor and related receptors on T cells, is known to amplify antigen-specific T cell responses (Michel, et al., Immunity, 15(6):935-45 (2001)).
T cell activation and function is also influenced by cytokines, the largest class of immunoregulatory molecules. Cytokines are secreted by activated antigen presenting cells after T cell encounters and impact expansion, survival, effector function, and memory of stimulated T cells (Pardoll, Nat. Rev. Immunol., 2(4):227-38 (2002); Fyfe, et al., J. Clin. Oncol., 13(3):688-96 (1995); Schluns, et al., Nat. Rev. Immunol, 3(4):269-79 (2003)).
While natural APCs, notably dendritic cells (DCs), are the most potent in initiating immune responses, their use in ex vivo stimulation of antigen-specific immune responses in clinical settings involving adoptive immunotherapy has been limited because of issues related to the quality, expense, and time involved in their isolation and culture (Oelke, et al., Nat. Med., 9(5):619-24 (2003)). Because T cell restriction necessitates the use of autologous DCs, custom isolation must be carried out for individual patient cases, limiting the generalization of this therapy. To address this issue, artificial APCs (“aAPCs”) have been proposed based on cellular and acellular systems and have been tested in the expansion of a number of specific T cell populations for the treatment of a variety of disease states (Oelke, et al., Nat. Med., 9(5):619-24 (2003); Kim, et al., Nat. Biotechnol., 22(4):403-10 (2004)).
Cellular aAPCs have been created from human leukemia cell lines (Hirano, et al., Clin. Cancer Res., 12(10):2967-75 (2006); Maus, et al., Nat. Biotechnol., 20(2):143-8 (2002)), insect cells (Mitchell, et al., J. Clin. Oncol., 20(4):1075-86 (2002); Jackson, et al., Proc. Natl. Acad. Sci. U.S.A., 89(24):12117-21 (1992); Sun, et al., Immunity, 4(6):555-64 (1996)), and mouse fibroblasts (Latouche, et al., Nat. Biotechnol., 18(4):405-9 (2000); Schoenberger, et al., Cancer Res., 58(14):3094-100 (1998)). Although physiological in nature, these systems require genetic modifications in order to effectively present antigens and may carry the risk for potential infection or tumorigenicity. Acellular approaches, which use micron-size latex or magnetic beads (Oelke, et al., Nat. Med., 9(5):619-24 (2003); Levine, et al., Science, 272(5270):1939-43 (1996); Tha, et al., J. Immunol. Methods, 249(1-2):111-9 (2001)) or lipid-based vesicles with immobilized ligands (van Rensen, et al., Pharm. Res., 16(2):198-204 (1999); Prakken, et al., Nat. Med., 6(12):1406-10 (2000); Thery, et al., Nat. Rev. Immunol., 2(8):569-79 (2002)), are attractive because of the flexibility in tailoring the composition and density of ligand presentation. While these platforms may eliminate the risk of infection by utilizing synthetic constructs, they lack biocompatibility and present safety risks if not removed prior to re-infusion of the expanded cells into patients (Kim, et al., Nat. Biotechnol., 22(4):403-10 (2004)). Also, there are currently no aAPC technologies that exist that incorporate all of the necessary signals for T cell activation in a safe, ready-to-use system that could be rapidly modified for antigen-specific T cell activation and expansion.
It is therefore an object of the invention to provide modular microparticulate aAPC compositions which provide for flexible addition and subtraction of elements.
It is another object of the invention to provide aAPCs and methods of use thereof for in vivo or ex vivo activation and expansion of lymphocytes, including T cells.
It is another object of the invention to provide compositions and methods for active and adoptive immunotherapy of cancer or an infection, such as a viral, bacterial, parasitic, protozoan or fungal infection.
It is another object of the invention to provide compositions and methods for the treatment of autoimmune disorders, graft rejection and graft-versus-host-disease.